This invention relates to therapeutic agents, and in particular to the use of compounds that are antagonists of the pain enhancing effects of E-type prostaglandins for the treatment or prevention of neuropathic pain. The invention also concerns the use of a compound that is an antagonist of the pain enhancing effects of E-type prostaglandins in the production of a medicament for use in the treatment or prevention of neuropathic pain. The invention further concerns a method of treating or preventing neuropathic pain by administration of an effective amount of an antagonist of the pain enhancing effects of E-type prostaglandins to a warm blooded animal such as man.
Neuropathic pain is a common clinical symptom associated with a variety of peripheral neuropathies and central nervous system injuries. Peripheral nerve injuries can arise directly from trauma, or indirectly from a wide range of diseases such as infections, cancer, metabolic conditions, toxins and musculoskeletal changes. Central nervous system injuries associated with neuropathic pain include stroke, trauma, Parkinson""s disease, multiple sclerosis and syringomyelia. The symptoms and signs of neuropathic pain include spontaneous/continuous pain, heightened cutaneous sensitivity (hyperesthesia), increased sensitivity with a lowering of the threshold to noxious stimulation (hyperalgesia), continued sensation of pain after the stimulus has ceased (hyperpathia), nociceptive response to innocuous stimulation (allodynia) and the presence of sensory deficits (hypoalgesia).
The treatment of neuropathic pain represents a significant therapeutic challenge Current clinical practice includes the use of a number of drug classes for the management of neuropathic pain, for example anticonvulsants, tricyclic antidepressants, and systemic local anaesthetics. However, the usual outcome of such treatment is partial or unsatisfactory pain relief, and in some cases the adverse effects of these drugs outweigh their clinical usefulness.
Classic analgesics are widely believed to be poorly effective or ineffective in the treatment of neuropathic pain. Few clinical studies on the use of non steroidal anti-inflammatory drugs (NSAIDs) or opiates in the treatment of neuropathic pain have been conducted, but in those which have, the results appear to indicate that NSAIDs are poorly effective or ineffective and opiates only work at high doses. A review analysing the controlled clinical data for peripheral neuropathic pain (PNP) (Pain, November, 1997 73(2), 123-39) reported that NSAIDs were probably ineffective as analgesics for PNP and that there was no long-term data supporting the analgesic effectiveness of any drug.
The development of a rodent model of peripheral mononeuropathy (Pain, 33, 1988, 87-107; Exp Brain Res, 113, 1997, 200-206; and Exp Brain Res, 120, 1998, 432-438) has provided a new approach for studies of post-injury neuropathic pain. The model produces neuropathic pain syndromes in the rat by loosely ligating the common sciatic nerve and has been described as a chronic constrictive injury (CCI) model. The behavioural, morphological and autoradiographic data obtained from the rodents in this model closely represent the clinical features of post-injury neuropathic pain. For example, the anticonvulsant gabapentin demonstrates activity in the CCI model (Eur J Pharmacol, 324, 1997, 157-160) and has been evaluated against neuropathic pain in humans (JAMA. 280, 1998, 1837-42; Clin J Pain. 13, 1997, 251-5). The NSAID ketorolac tromethamine possessed modest activity compared to morphine when dosed intrathecally (Can J Anaesth, 1996, 43, 967). This model has value therefore in predicting efficacy of compounds against neuropathic pain.